Less Chemotherapy May Be Best Choice for Some Patients with Colon Cancer : A shorter course of chemotherapy following surgery may be the preferred treatment for some patients with colon cancer, results of an international collaborative study suggest.

The findings come from an analysis of six concurrently run phase 3 clinical trials conducted in the United States, Europe, and Asia. Results of the analysisExit Disclaimer were presented June 4 at the American Society of Clinical Oncology annual meeting.

The nearly 13,000 patients in the trials had stage III colon cancer, meaning their tumors had progressed to the point that surgery alone is not considered sufficient to prevent the disease from recurring. For more than a decade, the standard of care for such patients has been 6 months of post-surgical, or adjuvant, chemotherapy.

But the analysis suggested that, for a large percentage of these patients—those whose cancer was considered to be at low risk of recurrence—3 months of adjuvant chemotherapy may be enough.

Patients with low-risk disease who had the shorter duration of either of two adjuvant chemotherapy regimens lived nearly as long without any evidence of their disease returning as patients who received the longer duration of treatment. And all patients, both high- and low-risk, treated with adjuvant therapy for 3 months had substantially lower rates of neuropathy—tingling, numbness, and pain in their hands, legs, and feet. Neuropathy is a common and troublesome long-term side effect of oxaliplatin, which is a key component of both adjuvant chemotherapy regimens used in the trials: FOLFOX and CAPOX.

Because of certain limitations with the study, oncologists at the ASCO meeting who treat colorectal cancer were not in universal agreement that the findings support a new standard of care.

The trial’s lead investigator, Axel Grothey, M.D., of the Mayo Clinic Cancer Center, however, said that he believes the trial results support that conclusion. And that for patients with high-risk disease, the study “provides a framework” for discussions about how to approach treatment.

Using Adjuvant Therapy
A diagnosis of stage III colon cancer means that the cancer has spread to nearby lymph nodes and the primary tumor has protruded into the bowel wall. When cancer cells are found in more than 3 lymph nodes, studies have shown that there is a high risk of the disease returning, and intensive post-surgical therapy is standard in such cases.

But if the disease has spread to three or fewer lymph nodes, the evidence has suggested that these patients are at a lower risk of their disease returning. Nevertheless, many of these patients have still been advised to undergo 6 months of an oxaliplatin-based chemotherapy regimen. The neuropathy induced by treatment with oxaliplatin can linger for years and can often be debilitating, dramatically affecting patients’ quality of life, Dr. Grothey said.

Testing Whether Less is Okay
In 2007, the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration was established to gather enough clinical trial data to establish whether 3 months of adjuvant chemotherapy would be no less effective than, or non-inferior to, 6 months of adjuvant treatment in patients with stage III colon cancer. The six clinical trials conducted under the IDEA umbrella, which includes the NCI-funded CALGB/SWOG trial 80702, all randomly assigned patients with stage III colon cancer to 3 months or 6 months of adjuvant chemotherapy.

Funded entirely with public or philanthropic support, IDEA is the largest prospective study in colorectal cancer research ever conducted, Dr. Grothey said.

In the analysis of all the patients in the six trials, the 3-month adjuvant treatment course fell just short of the statistical bar to be considered non-inferior to 6 months of chemotherapy, with 74.6% of patients free of evidence of recurrence, known as disease-free survival, compared with 75.5% in the 6-month group.

But for patients with low-risk colon cancer, who accounted for about 60% of patients in the trials, at 3 years there was virtually no difference in disease-free survival: 83.1% versus 83.3%.

In addition, patients who received the shorter course of adjuvant therapy had dramatically lower rates of moderate to severe peripheral neuropathy. Neuropathy occurred nearly three times as often in patients who received 6 months of adjuvant therapy, Dr. Grothey reported, although there were slight differences in neuropathy rates according to the adjuvant regimen used.

Practice Changing?
Andrew Epstein, M.D., who treats patients with gastrointestinal cancers at Memorial Sloan Kettering Cancer Center, agreed with Dr. Grothey that practice should change based on the IDEA results.

“Even in high-risk patients, it’s now even more appropriate to consider less than 6 months” of adjuvant therapy, Dr. Epstein said. Those patients might include patients with pre-existing neuropathy or who have other issues or symptoms, such as low blood cell count (cytopenia) or fatigue, he explained. “Most patients can’t tolerate 6 months of oxaliplatin,” Dr. Epstein said. “So I really welcome a set of data that will lessen the drive to give patients 6 months of therapy.”

Not all experts, however, were as convinced.

Cathy Eng, M.D., associate director of the Colorectal Center at the University of Texas MD Anderson Cancer Center, pointed to several of the study’s shortcomings.

They included that study failed to achieve its primary aim of demonstrating non-inferiority of the 3-month regimens and that breaking down the analysis by different risk groups was not included in the study’s original design. Dr. Eng also noted that much of the data on the CAPOX regimen came from only one of the six trials included in IDEA, called SCOT, results of which were also presentedExit Disclaimer at the meeting.

Because of these limitations, “you can’t say that 3 months [of adjuvant therapy] is definitively non-inferior to 6 months,” she said during a discussion session on the trial at the ASCO meeting.

Much of the debate about length of treatment is somewhat moot, researchers and clinicians at the meeting seemed to agree.

For example, in his own practice, Dr. Epstein said his patients with stage III disease rarely receive the full 6 months of adjuvant therapy. Treatment only extends the full 6 months “in patients who are tolerating it well,” he added. And even for those patients, Dr. Epstein said he regularly counsels them about the risk of neuropathy that comes on after treatment has ended, known as delayed-onset neuropathy.

The IDEA analysis also showed that patients who received CAPOX for 3 months had slightly longer 3-year disease-free survival than patients who underwent 6 months of CAPOX adjuvant therapy. However, CAPOX is not commonly used in the United States, Dr. Grothey said. In addition to oxaliplatin, the CAPOX regimen also uses capecitabine, which has a higher insurance co-pay for patients and often “has higher toxicities compared to FOLFOX,” he continued.

Use of the FOLFOX regimen also requires surgically implanting a port to allow for outpatient infusions.

So, moving forward, Dr. Grothey said, in the case of CAPOX, “patients might be willing to go through more side effects…to not have [port implantation] surgery and to only undergo 3 months of treatment.”

Less Chemotherapy May Be Best Choice for Some Patients with Colon Cancer